Obesity is an epidemic and a major cause of morbidity and mortality. However, data indicates that body adiposity is normally very tightly regulated. A current model of energy homeostasis is of negative adiposity feedback signaling . The hormones insulin and leptin circulate in proportion to body adiposity and signal energy excess to the central nervous system. By activating their respective receptors on neuronal subsets found in the hypothalamus and elsewhere, these hormones lower food intake and increase energy expenditure. Obesity is accompanied by CNS insulin and leptin resistance and NF-xB like signaling. Peroxisome proliferator activated receptors (PPAR) are nuclear receptors that are the target of drugs used clinically to treat diabetes and dyslipidemia. Interestingly, PPARy is also expressed in the central nervous system, and its expression is enriched in mediobasal hypothalamic neurons that are known to be important for energy homeostasis. Fatty acids, including polyunsaturated fatty acids, are known to activate PPARy. Since PPARy is a) an insulin sensitizer in peripheral tissues and b) known to antagonize NF-KB signaling in the CNS, we hypothesize that PPARy in the CNS plays a protective role in the development of diet induced obesity. Preliminary data indicates a neuron specific PPARy knock-out mouse, developed utilizing a published, floxed PPARy allele mated with Nestin-Cre driver mice are more susceptible to diet induced obesity (DIO). The aims of this proposal are to determine the mechanism for increased susceptibility to DIO in neuronal PPARy KO mice and to determine whether elimination of PPARy in AGRP or POMC neurons recapitulates the neuronal PPARy phenotype. If genetic ablation of CNS PPARv is found to impact parameters of energy homeostasis, this will be indicative of a role for PPARy in CNS insulin sensitivity. Such a finding would have far reaching implications, first, supporting the idea that dietary fats, via their action on PPARy have physiological effects that extend beyond their basic nutritional profile. Specific dietary fatty acids serve as potent ligands for PPARy and a positive finding would support the a "nutrapharmaceutical" approach in the treatment of diabetes and obesity. If a role for PPARy in CNS controlled energy homeostasis is indicated, this will establish the brain as yet another target of PPARy agonist drugs.